2021
The E3 ubiquitin ligase RNF186 and RNF186 risk variants regulate innate receptor-induced outcomes
Ranjan K, Hedl M, Abraham C. The E3 ubiquitin ligase RNF186 and RNF186 risk variants regulate innate receptor-induced outcomes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2013500118. PMID: 34353900, PMCID: PMC8364215, DOI: 10.1073/pnas.2013500118.Peer-Reviewed Original ResearchMeSH KeywordsCytokinesHumansImmunity, InnateInflammatory Bowel DiseasesIntestinesMacrophagesMyeloid CellsNF-kappa BNod2 Signaling Adaptor ProteinPolymorphism, Single NucleotideReceptor-Interacting Protein Serine-Threonine Kinase 2Receptors, Pattern RecognitionToll-Like Receptor 2Toll-Like Receptor 4UbiquitinationUbiquitin-Protein LigasesConceptsPattern recognition receptorsE3 ubiquitin ligase activityStimulation of PRRsAntimicrobial reactive oxygen speciesMultiple pattern recognition receptorsLoss of functionLigase activityReactive nitrogen speciesComplex assemblyIntestinal myeloid cellsReactive oxygen speciesAutophagy pathwayDownstream signalingRNF186Bacterial clearanceRisk variantsRecognition receptorsHuman macrophagesOxygen speciesInnate immunityInflammatory bowel diseaseNitrogen speciesMicrobial clearanceSpeciesMyeloid cells
2019
IL23 induces IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomes
Sun R, Hedl M, Abraham C. IL23 induces IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomes. Gut 2019, 69: 264. PMID: 31097538, PMCID: PMC6858485, DOI: 10.1136/gutjnl-2018-316830.Peer-Reviewed Original ResearchConceptsMonocyte-derived macrophagesHuman monocyte-derived macrophagesJanus kinase/signal transducerKinase/signal transducerDynamin-mediated endocytosisReceptor-induced signalingCell surface regulationR381Q variantIBD pathogenesisIntestinal myeloid cellsLate endosomesPattern recognition receptorsSignal transducerPathway membersDefines mechanismsReal-time PCRCell typesHeLa cellsSignalingKey playersRNA expressionHuman macrophagesPathwayWestern blotMyeloid cells
2015
MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation
Lahiri A, Hedl M, Abraham C. MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 10461-10466. PMID: 26240347, PMCID: PMC4547281, DOI: 10.1073/pnas.1501752112.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAutophagyCaspase 1CytokinesEnzyme ActivationGene Expression RegulationGenetic Predisposition to DiseaseGenotypeHomeostasisHumansInflammationInflammatory Bowel DiseasesLeukocytes, MononuclearLigandsMacrophagesMonocytesProtein Structure, TertiaryProtein Tyrosine Phosphatases, Non-ReceptorRisk FactorsRNA, Small InterferingSignal TransductionToll-Like ReceptorsConceptsPattern recognition receptorsCaspase-1 activationInflammatory bowel diseaseMTMR3 expressionReceptor-induced signalingHost pattern recognition receptorsCytokine secretionMultiple genetic lociPhosphatase domainMicrobial interactionsGenetic lociMTMR3Undefined roleAutophagyIL-1β secretionRecognition receptorsHuman macrophagesAutophagy levelEnhanced autophagyProtein 3Bowel diseaseCytokine productionRisk polymorphismsRisk allelesAltered functionA TPL2 (MAP3K8) disease-risk polymorphism increases TPL2 expression thereby leading to increased pattern recognition receptor-initiated caspase-1 and caspase-8 activation, signalling and cytokine secretion
Hedl M, Abraham C. A TPL2 (MAP3K8) disease-risk polymorphism increases TPL2 expression thereby leading to increased pattern recognition receptor-initiated caspase-1 and caspase-8 activation, signalling and cytokine secretion. Gut 2015, 65: 1799. PMID: 26215868, PMCID: PMC5106344, DOI: 10.1136/gutjnl-2014-308922.Peer-Reviewed Original ResearchConceptsCaspase-8 activationMonocyte-derived macrophagesAutocrine IL-1βIL-18 secretionHost-microbial interactionsCytokine secretionHuman monocyte-derived macrophagesHuman myeloid cellsMyeloid cellsCaspase-1Intestinal myeloid cellsPattern recognition receptorsOligomerisation domainIL-1βPrimary human myeloid cellsReal-time PCRFunctional consequencesTpl2NFκB signalingRecognition receptorsRNA expressionIntestinal immune homeostasisERKMyeloid-derived cellsJNK
2014
Activation of Pattern Recognition Receptors Up-Regulates Metallothioneins, Thereby Increasing Intracellular Accumulation of Zinc, Autophagy, and Bacterial Clearance by Macrophages
Lahiri A, Abraham C. Activation of Pattern Recognition Receptors Up-Regulates Metallothioneins, Thereby Increasing Intracellular Accumulation of Zinc, Autophagy, and Bacterial Clearance by Macrophages. Gastroenterology 2014, 147: 835-846. PMID: 24960189, PMCID: PMC4170054, DOI: 10.1053/j.gastro.2014.06.024.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnti-Bacterial AgentsAutophagyCaspase 1Cells, CulturedDNA-Binding ProteinsGene Expression RegulationHumansIntestinal MucosaIntestinesMacrophagesMetallothioneinMiceMice, Inbred C57BLMice, KnockoutNF-kappa BNod2 Signaling Adaptor ProteinRNA InterferenceTime FactorsToll-Like ReceptorsTranscription FactorsTransfectionZincConceptsMetal-regulatory transcription factor 1Human monocyte-derived macrophagesPattern recognition receptorsMonocyte-derived macrophagesIntracellular zincMyeloid-derived cellsSmall interfering RNAsBacterial clearanceGentamicin protection assaysInduction of autophagyTranscription factor 1Metallothionein geneMultiple genesInterfering RNAsIntestinal macrophagesSpecific proteinsOligomerization domain 2Domain 2Toll-like receptor 5AutophagyIntestinal lamina propria cellsContinuous stimulationSpecific pathogen-free facilityProtection assaysInduces expressionPattern Recognition Receptor Signaling in Human Dendritic Cells is Enhanced by ICOS Ligand and Modulated by the Crohn’s Disease ICOSLG Risk Allele
Hedl M, Lahiri A, Ning K, Cho JH, Abraham C. Pattern Recognition Receptor Signaling in Human Dendritic Cells is Enhanced by ICOS Ligand and Modulated by the Crohn’s Disease ICOSLG Risk Allele. Immunity 2014, 40: 734-746. PMID: 24837102, PMCID: PMC4157904, DOI: 10.1016/j.immuni.2014.04.011.Peer-Reviewed Original ResearchMeSH KeywordsCells, CulturedCrohn DiseaseDendritic CellsEnzyme ActivationGTP-Binding ProteinsHL-60 CellsHumansInducible T-Cell Co-Stimulator LigandInducible T-Cell Co-Stimulator ProteinJNK Mitogen-Activated Protein KinasesMacrophagesNeoplasm ProteinsNF-kappa BNod2 Signaling Adaptor ProteinPhosphorylationPolymorphism, Single NucleotideProtein Kinase CReceptors for Activated C KinaseReceptors, Cell SurfaceReceptors, Pattern RecognitionRNA InterferenceRNA, Small InterferingSignal TransductionConceptsMonocyte-derived dendritic cellsInflammatory bowel diseaseCytokine secretionDendritic cellsImmune homeostasisICOS ligandHuman monocyte-derived dendritic cellsPattern recognition receptor signalingRisk allelesIntestinal immune homeostasisCrohn's disease phenotypeHuman dendritic cellsCostimulatory molecule ICOSOligomerization domain 2NF-κB activationDisease phenotypePattern recognition receptorsICOSL expressionBowel diseaseReceptor signalingRisk carriersSecretionHomeostasisKinases PKCSignaling